Process for the synthesis of 2-amino-5-chloro-3-methylbenzoic acid catalyzed by scandium

Abstract

The application provides a process for synthesizing 2-amino-5-chloro-3-methylbenzoic acid by using scandium as a catalyst. 2-amino-5-chloro-3-methylbenzoic acid is obtained by oxidizing 2-amino-3-methylbenzoic acid hydrochloride under the action of a catalyst and hydrogen peroxide. The method can catalyze the preparation of 2-amino-5-chloro-3-methylbenzoic acid by high-selectivity oxidation and chlorination, and has a good industrial application prospect due to mild reaction conditions.

Description

TECHNICAL FIELD

[0001] The present application relates to a process for the catalytic synthesis of 2-amino-5-chloro-3-methylbenzoic acid, in particular to a method for the catalytic oxidation of chlorinated 2-amino-3-methylbenzoic acid to prepare 2-amino-5-chloro-3-methylbenzoic acid. BACKGROUND

[0002] 2-amino-5-chloro-3-methylbenzoic acid is mainly used as an important intermediate for the synthesis of chlorantraniliprole, cyantraniliprole, tetraniliprole, etc. This class of insecticides has a completely new insecticidal principle that other insecticides do not have, and can efficiently activate the fishy (muscle) receptors of insects. Excessive release of calcium ions in the intracellular calcium pool leads to the paralysis and death of insects, and has high activity on the larvae of lepidopteran pests, a wide insecticidal spectrum, good persistence, and no cross-resistance with traditional insecticides. This class of products has rapidly occupied the market with its unique action mechanism, outstanding product performance, and has established a strong market position in the field of lepidopteran pest control. In addition, this compound can be used to synthesize other organic compounds with biological activity, such as drug molecules, antibiotics, anti-inflammatory drugs, etc., and can also be used to synthesize dye intermediates.

[0003] Chinese patent document CN201910370497.9 discloses a continuous synthesis method of 2-amino-5-chloro-3-methylbenzoic acid. 2-amino-5-chloro-3-methylbenzoic acid is obtained by using 2-amino-3-methylbenzoic acid as the starting material and cyanuric chloride as the chlorine source. This method has simple and readily available raw materials, simple post-processing, and high overall yield, and can provide an important reference for industrial production. However, the reaction efficiency is too low due to the addition of 5 times the volume of solvent to the substrate, and the reaction time is relatively long.

[0004] Chinese patent document CN202011607636.4 discloses a synthesis method of 2-amino-5-chloro-3-methylbenzoic acid. 2-amino-3-methyl-5-chlorobenzoic acid is obtained by mixing 2-amino-3-methylbenzoic acid, dichloroguanidine, benzoyl peroxide and DMF and performing a chlorination reaction. This process has high reaction efficiency, but the chlorine source is relatively expensive and requires high temperature of 90℃.

[0005] Chinese patent document CN202410032745.X discloses a synthesis method of 2-amino-5-chloro-3-methylbenzoic acid. N,N-dimethylformamide is used as a solvent, N-chlorosuccinimide is used as a substrate, and 2-amino-3-methylbenzoic acid is used as a raw material. The materials are mixed uniformly by a micro-mixer, then filtered, dried and purified to obtain the product. The continuous synthesis of 2-amino-5-chloro-3-methylbenzoic acid by this method has the advantages of simple flow, short reaction time, good product selectivity and high raw material conversion rate. However, the required temperature is relatively high and the chlorinating reagent is relatively expensive.

[0006] Donya Khaledian et al. successfully synthesized the first magnetic core-shell scandium nanocatalyst by immobilizing scandium triflate on sodium benzenesulfonate functionalized magnetic nanoparticles. The catalyst showed excellent activity in the oxidation of sulfides to sulfoxides by H2O2(Catalysis Communications 124(2019)46-50).

[0007] Jiaxiang Chu et al. synthesized a coordination unsaturated scandium terminal imine complex. This alkali-free scandium terminal imine complex has very high reactivity, especially for the activation of C-H bonds of terminal olefins. In addition, it can undergo cycloaddition reaction with internal alkynes and initiate dehydrofluorination reaction of fluorosubstituted benzene or alkane at room temperature(Am. Chem. Soc. 2014, 136, 10894-10897).

[0008] Therefore, scandium triflate is used as a Lewis acid catalyst to be added to the system of the oxidative chlorination reaction, so as to enhance the acidity of the reaction system, so that the reaction can still maintain high conversion rate and selectivity under mild conditions. In the synthesis method of 2-amino-5-chloro-3-methylbenzoic acid being used, there are problems such as high reaction temperature, expensive chlorine source or excessive solvent. Therefore, in order to solve these problems, it is necessary to develop a new method which is mild in reaction conditions, green and environmentally friendly, simple and efficient, and low in cost. SUMMARY

[0009] The purpose of the present application is to solve the above problems. Through retrieval, we found that Lewis acid catalysts have attracted great attention due to their unique activity and selectivity in the synthesis of organic compounds under mild reaction conditions. Scandium triflate, as a promising mild, potent and selective Lewis acid, is introduced into various functional group transformations, and we use a silica shell to encapsulate scandium triflate, reducing the leaching of active components. Therefore, we provide a scandium-catalyzed process for synthesizing 2-amino-5-chloro-3-methylbenzoic acid. By controlling the reaction conditions, high conversion rate and selectivity are achieved, which has good industrial prospects.

[0010] The technical scheme of the present application is: a process for synthesizing 2-amino-5-chloro-3-methylbenzoic acid by scandium catalysis, which comprises the following steps: A preparation of a catalyst: dissolve scandium triflate in water, add a carrier, stir until uniform, and dry; dissolve a silicon source in an organic solvent, add the above-mentioned solid powder, stir until uniform, and dry to obtain a solid; and dry to obtain a scandium triflate catalyst, wherein the mass of scandium triflate accounts for 13-30% of the total mass of the catalyst; B preparation of 2-amino-5-chloro-3-methylbenzoic acid: add a substrate 2-amino-3-methylbenzoic acid, hydrochloric acid, a solvent, an oxidizing agent, and the scandium triflate catalyst in a reaction container, react at a certain reaction temperature for a period of time, separate phases, distill, and purify to obtain the product 2-amino-5-chloro-3-methylbenzoic acid.

[0011] Preferably, the mass ratio of scandium triflate to the silicon source in step A is 1:(1.2-4).

[0012] Preferably, the carrier in step A is silicon dioxide or activated carbon; and the silicon source is tetraethyl orthosilicate or silicic acid.

[0013] Preferably, the drying temperature in step A is 120-180°C; and the stirring time is 3-5h.

[0014] Preferably, the oxidizing agent in step B is hydrogen peroxide; the molar ratio of the substrate 2-amino-3-methylbenzoic acid to hydrogen peroxide is 1:(1.2-2); and the added mass of the catalyst is 3-7% of the mass of the substrate.

[0015] Preferably, the molar ratio of the substrate 2-amino-3-methylbenzoic acid to hydrochloric acid is 1:(1.5-3.5).

[0016] Preferably, the solvent is water, acetonitrile, or 1,4 dioxane; and the mass ratio of the substrate 2-amino-3-methylbenzoic acid to the solvent is 1:(1-2.1).

[0017] Preferably, the reaction temperature in step B is 25-60°C; and the reaction time is 5-10h.

[0018] The principle of the present application is shown in formula 1.

[0019]

[0020] Advantages:

[0021] The application is a method for preparing 2-amino-5-chloro-3-methylbenzoic acid with high selectivity by scandium catalytic oxidation chlorination. The method selects appropriate amount of hydrochloric acid as a chlorine source, and under the dual action of a catalyst and hydrogen peroxide, the hydrochloric acid is oxidized to chlorine, and then the chlorine atom is selectively added to the benzene ring. By controlling the reaction conditions, a high yield is achieved. The process is simple, efficient, mild, high-yielding, low-risk, low-equipment requirement, low-cost, and suitable for industrial production. DETAILED DESCRIPTION

[0022] Embodiment 1:

[0023] Scandium triflate 50 g was added to 1 L of water, and 100 g of silicon dioxide was added, stirred for 5 h, and dried at 180 ℃. Tetraethyl orthosilicate 60 g was dissolved in 500 ml of dichloromethane, and the above solid powder was added, stirred for 5 h. The solid was evaporated to dryness, and the catalyst A was obtained by drying at 180 ℃ (the mass ratio of scandium triflate to silicon source was 1:1.2, and the loading amount of scandium triflate was 30%).

[0024] Embodiment 2:

[0025] The amount of scandium triflate was reduced to 25 g, tetraethyl orthosilicate 100 g was dissolved in 500 ml of dichloromethane, and the rest of the operation was carried out according to embodiment 1, and catalyst B was obtained by drying (the mass ratio of scandium triflate to silicon source was 1:4, and the loading amount of scandium triflate was 15%).

[0026] Embodiment 3

[0027] Tetraethyl orthosilicate was replaced by an equal amount of silicic acid, and the rest of the operation was carried out according to embodiment 1, and catalyst C was obtained by drying (the mass ratio of scandium triflate to silicon source was 1:1.2, and the loading amount of scandium triflate was about 30%).

[0028] Embodiment 4

[0029] Both drying temperatures were changed to 120 ℃, and the rest of the operation was carried out according to embodiment 1, and catalyst D was obtained by drying (the mass ratio of scandium triflate to silicon source was 1:1.2, and the loading amount of scandium triflate was 30%).

[0030] Embodiment 5:

[0031] Silicon dioxide was replaced by an equal amount of activated carbon, and the rest of the operation was carried out according to embodiment 1, and catalyst E was obtained by drying (the mass ratio of scandium triflate to silicon source was 1:1.2, and the loading amount of scandium triflate was 30%).

[0032] Embodiment 6:

[0033] The stirring time was changed to 3h, and the rest of the operations were performed according to Embodiment 1. The dried catalyst was catalyst F (the mass ratio of scandium triflate to silicon source was 1:1.2, and the scandium triflate loading was 30%).

[0034] Embodiment 7:

[0035] In a glass reaction vessel, 151 g (1 mol) of the substrate 2-amino-3-methylbenzoic acid, 250 g (2.5 mol) of hydrochloric acid (36.5%), 5 g of catalyst A, 200 mL (157 g) of acetonitrile, and 136 g (1.2 mol) of hydrogen peroxide (30%) were added dropwise with stirring at a slow rate. The reaction vessel was sealed and placed in a 25°C water bath for 5 h. After the reaction was completed, the catalyst was separated by centrifugation. The liquid phase was neutralized with sodium carbonate, and the excess hydrochloric acid was extracted with ethyl acetate three times. The organic phase was combined and the solvent was removed under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 154 g, with a yield of 83%.

[0036] Embodiment 8:

[0037] The catalyst was changed to catalyst B, and the rest of the operations were performed according to Embodiment 7. The solvent was removed under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 145 g, with a yield of 78%.

[0038] Embodiment 9:

[0039] The catalyst was changed to catalyst C, and the rest of the operations were performed according to Embodiment 7. The solvent was removed under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 149 g, with a yield of 80%.

[0040] Embodiment 10:

[0041] The catalyst was changed to catalyst D, and the rest of the operations were performed according to Embodiment 7. The solvent was removed under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 153 g, with a yield of 82%.

[0042] Embodiment 11:

[0043] The catalyst was changed to catalyst E, and the rest of the operations were performed according to Embodiment 7. The solvent was removed under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 149 g, with a yield of 80%.

[0044] Embodiment 12:

[0045] The catalyst was changed to catalyst F, and the rest of the operations were performed according to Embodiment 7. The solvent was removed under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 153 g, with a yield of 82%.

[0046] Embodiment 13:

[0047] The reaction temperature was changed to 60°C and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 163 g in 88% yield.

[0048] Example 14:

[0049] The amount of hydrogen peroxide was changed to 227 g (2 mol) and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 162 g in 87% yield.

[0050] Example 15:

[0051] The reaction time was changed to 10 h and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 160 g in 86% yield.

[0052] Example 15:

[0053] The amount of catalyst was changed to 10 g and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 162 g in 87% yield.

[0054] Example 16:

[0055] The amount of hydrochloric acid was changed to 150 g (1.5 mol) and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 149 g in 80% yield.

[0056] Example 17:

[0057] The amount of hydrochloric acid was changed to 350 g (3.5 mol) and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 158 g in 85% yield.

[0058] Example 18:

[0059] The amount of acetonitrile was changed to 400 ml (314 g) and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 139 g in 75% yield.

[0060] Example 19:

[0061] The solvent was changed to water (200 g) and the rest of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to obtain 2-amino-5-chloro-3-methylbenzoic acid 147 g in 79% yield.

[0062] Example 20:

[0063] The solvent was changed to an equal volume of 1,4 dioxane (207 g) and the remainder of the procedure was as described in Example 7. The solution was evaporated under reduced pressure to give 2-amino-5-chloro-3-methylbenzoic acid 158 g in 85% yield.

[0064] Example 21:

[0065] The catalyst after the reaction in Example 13 was removed by centrifugation and reused. The process flow was the same as Example 13 and samples were taken for gas chromatography analysis. The results of the analysis of the products are shown in Table 1.

[0066] Example 22:

[0067] The catalyst after the reaction in Example 8 was removed by centrifugation and reused. The process flow was the same as Example 8 and samples were taken for gas chromatography analysis. The results of the analysis of the products are shown in Table 2.

[0068] Table 1. Catalyst reuse in Example 20

[0069] Number of recoveries Yield 1 88％ 2 85％ 3 86％ 4 84％ 5 80％

[0070] Table 2. Catalyst reuse in Example 21

[0071] Number of recoveries Yield 1 78％ 2 77％ 3 74％ 4 76％ 5 72％

Claims

1. A process for the scandium-catalyzed synthesis of 2-amino-5-chloro-3-methylbenzoic acid, comprising the following steps: A. Catalyst preparation: Scandium trifluoromethanesulfonate is dissolved in water, added to a support, stirred evenly, and dried; a silicon source is dissolved in an organic solvent, added to the above solid powder, and stirred evenly; the solid is evaporated to dryness, and then dried to obtain the scandium trifluoromethanesulfonate catalyst, wherein the mass of scandium trifluoromethanesulfonate accounts for 13-30% of the total mass of the catalyst; B. Preparation of 2-amino-5-chloro-3-methylbenzoic acid: 2-amino-3-methylbenzoic acid, hydrochloric acid, solvent, oxidant, and scandium trifluoromethanesulfonate catalyst are added to a reaction vessel, reacted at a certain reaction temperature for a period of time, and the product 2-amino-5-chloro-3-methylbenzoic acid is obtained by phase separation, distillation, and purification; wherein the support mentioned in step A is silica or activated carbon; the silicon source is tetraethyl silicate or silicic acid; and the oxidant mentioned in step B is hydrogen peroxide.

2. The process according to claim 1, characterized in that... In step A, the mass ratio of scandium trifluoromethanesulfonate to silicon source is 1:(1.2-4).

3. The process according to claim 1, characterized in that... The drying temperature in step A is 120℃-180℃; the stirring time is 3-5 hours.

4. The process according to claim 1, characterized in that... The molar ratio of the substrate 2-amino-3-methylbenzoic acid to hydrogen peroxide in step B is 1:(1.2-2); the mass of the catalyst added is 3%-7% of the substrate mass.

5. The process according to claim 1, characterized in that... The molar ratio of the substrate 2-amino-3-methylbenzoic acid to hydrochloric acid is 1:(1.5-3.5).

6. The process according to claim 1, characterized in that... The solvent is water, acetonitrile, or 1,4-dioxane; the mass ratio of the substrate 2-amino-3-methylbenzoic acid to the solvent is 1:(1-2.1).

7. The process according to claim 1, characterized in that... The reaction temperature in step B is 25℃-60℃; the reaction time is 5h-10h.

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